Sjogren’s SyndromeKey Concepts for internists

Update in Internal MedicineUniversity of Pittsburgh Medical Center

October 19, 2017

Ghaith Noaiseh, MD

Director. UPMC Sjogren’s Syndrome Clinic

Assistant Professor of Medicine Division of Rheumatology and clinical Immunology

University of Pittsburgh Medical Center

Financial disclosures

• No consulting fees

• Study site Co-Investigator:- HGS- BMS- Medimmune- Astra Zeneca - Ablynx- Pfizer

Henrik Sjögren

19 cases of keratoconjunctivitis sicca including two cases with swelling of the major salivary glands

Sjögren H: Zur kenntnis der keratoconjunctivitis sicca. Acta Ophthalmol 1933

As of August 14th 2013

Challenges in Diagnosis

• Diagnosis frequently delayed

• Diagnosis often preceded by Dx of other AIRD• Misdiagnosis / under-diagnosis• Lack of understanding of disease spectrum• Certain subsets of disease more challenging

to diagnose

Epidemiology

• Prevalence : 0.01% and 0.72%

Maldini, C. et al. Arthritis Care Res. (Hoboken) (2014)Kabasakal, Y. et al. Scand. J. Rheumatol. (2006)

• Peak incidence: 5th – 6th decades of life

• F : M ratio 10-20 : 1Bowman SJ et al. Scand J Rheumatol (2004)

Pathophysiology

Autoimmune epithelitis

• Glandular epithelial cells (EC) as a key player

• Activated EC act as a non-professional APC

• Other organs: Kidney, liver, lungs, thyroid may be involved with ECs as primary target

Moutsopoulos HM. Clin Immuno Immunopath. (2004)

The pathogenesis of autoimmune epitelitis as a potential explanation for SS

Brito-Zerón, P. et al. Nat. Rev. Dis. Primers (2016)

The pathogenesis of autoimmune epitelitis as a potential explanation for SS

Brito-Zerón, P. et al. Nat. Rev. Dis. Primers (2016)

Pathogenesis models of salivary gland inflammation in SS

A. Glandular hypofunction explained by tissue losssecondary to immune attack, resulting in cytotoxic cell death and apoptosis

B. Glandular hypofunction results from downregulation of receptor - mediated secretion of salivary fluid into the ductal lumen.

St. Clair. W. in Kelley’s textbook of Rheumatology 9th ed

Clinical manifestations

The spectrum of Sjogren’s syndrome

SiccaFatigue Pain (Most patients)

Extraglandularmanifestations(30-40%) - ILD- Interstitial

nephritis

Vasculitic features- Glomerulonephritis- Mononeuritis

multiplex - LCV

Lymphoma(5%)

Dry eyes • Grittiness • Foreign body sensation• Burning• Photophobia• Corneal perforation in severe cases

Tincani et al. BMC Medicine (2013)

Rolando M. et al. Survey of Ophthalmo. (2001)

Tincani et al. BMC Medicine 2013

Dry mouth

• Difficulty chewing, swallowing dry food • Altered taste (metallic, salty, bitter)• Problems wearing dentures• Dysphagia (confused with pharyngeal dysphagia) • Rampant dental caries, loose fillings

• Atrophic oral candidiasis

Rischmueller M. et al Best Prac Res Clin Rheum (2016)

Other exocrine gland dysfunction

• Upper airways: - Nasal obstruction, dryness - Hoarseness - Cough

• Vagina:- Dyspareunia- Recurrent candidiasis

• Skin: - Xerosis cutis

Salivary gland enlargement

• Parotid or submandibular: in 25-35 %• Usually painless • Unilateral or bilateral

• Asymmetric enlargement may indicate a neoplasm (lymphoma)

Rischmueller M. et al Best Prac Res Clin Rheum (2016)

Parotid Gland EnlargementDifferential diagnosis

Sialadenitis Sialadenosis

• Sarcoidosis• IgG4-related diseases

• Viral infections (Mumps, HIV)• Bacterial

• Primary B and T cell lymphoma• Multicentric Castleman's disease• Malignant carcinoma• Benign tumors

• Calculus duct obstruction

• Alcoholism

• Chronic liver disease

• Diabetes mellitus

• Bulemia Nervosa

Clinical Hallmarks - The triad

1. Sicca syndrome 2. Fatigue3. MSK Pain

• One or more is present in almost all patients• Main drivers of morbidity• May be confused with fibromyalgia

Systemic Manifestations

• 25-40% of patients• More likely in anti SSA

Kassan S. et al. Arch Intern Med. (2004)

• Predictor of extraglandular manifestation and poor outcome

Hughes M et al. Best Prac Res Clin Rheum. (2016)

Joint involvement

• Inflammatory arthralgia• True arthritis: Resembles RA

- Usually non-erosive - Can be Relapsing-remitting

• Subclinical synovitis in 30% on ultrasound

Ramos-Casals M et al. Rheumatology. (2015)

www.plosone.org

Pulmonary involvement

Neurological manifestations

Sjogren’s syndrome patients may develop which of the following complications:

1. Sensory peripheral neuropathy2. Mononeuritis multiplex3. CIDP4. Autonomic neuropathy 5. All of the above

Neurological manifestations

Sjogren’s syndrome patients may develop which of the following complications:

1. Sensory peripheral neuropathy2. Mononeuritis multiplex3. CIDP4. Autonomic neuropathy 5. All of the above

www.hopkinsmedicine.org

Erythema Annulare (similar to subacute cutaneous lupus rash)

www.clevelandclinicmeded.com

Skin Manifestations

Leucocytoclastic vasculitis

Renal Manifestations

The most common renal involvement in Sjogren’s syndrome is:

1. Pauci-immune crescentic glomerulonephritis2. FSGS3. IN leading to Renal tubular acidosis Type I4. IN leading to Renal tubular acidosis Type 25. Non of the above

Renal Manifestations

The most common renal involvement in Sjogren’s syndrome is:

1. Pauci-immune crescentic glomerulonephritis2. FSGS3. IN leading to Renal tubular acidosis Type I4. IN leading to Renal tubular acidosis Type 25. Non of the above

Associated non-Rheumatic Diseases

• Autoimmune thyroid disease: most common • Autoimmune hepatitis - Primary Biliary Cirrhosis • Celiac disease• Autoimmune adrenal gland disease• Autoimmune hypophysitis• Pernicious anemia

Lymphoma in Sjogren’s syndrome

Histological types

• Mostly low-grade B cell NHL marginal zone mucosa-associated lymphoid tissue (MALT) lymphomas

• Often develops in organs where SS is active

• Germinal center-like structures is a risk factor

Nocturne G et al. Br J Haematol (2015)

Risk indicators for lymphoma development

Brito-Zerón, P. et al. Nat. Rev. Dis. Primers (2016)

Clinical features:• Persistent parotid gland enlargement• Purpura• European League Against Rheumatism Sjögren syndrome Disease Activity Index(ESSDAI) score of ≥5

Genetic polymorphisms:• TNFSF13B• TNFRSF13C• TNFAIP3

Histopathological features:• Presence of germinal centers in the MSGB• Focus score of >3

Laboratory abnormalities:• CD4+ lymphopaenia

Immunological findings:• Low complement C3 or C4 levels• Mixed cryoglobulinaemia• MGUS• Increased lymphocyte-related cytokine levels (including BAFF,FMS-like tyrosine kinase 3 ligand, CXCL 13 and CXCL 11)• Increased β2-microglobulin levels• Presence of rheumatoid factor

Risk indicators for lymphoma development

Brito-Zerón, P. et al. Nat. Rev. Dis. Primers (2016)

Clinical features:• Persistent parotid gland enlargement• Purpura• European League Against Rheumatism Sjögren syndrome Disease Activity Index(ESSDAI) score of ≥5

Genetic polymorphisms:• TNFSF13B• TNFRSF13C• TNFAIP3

Histopathological features:• Presence of germinal centers in the MSGB• Focus score of >3

Laboratory abnormalities:• CD4+ lymphopaenia

Immunological findings:• Low complement C3 or C4 levels• Mixed cryoglobulinaemia• MGUS• Increased lymphocyte-related cytokine levels (including BAFF,FMS-like tyrosine kinase 3 ligand, CXCL 13 and CXCL 11)• Increased β2-microglobulin levels• Presence of rheumatoid factor

Risk indicators for lymphoma development

Brito-Zerón, P. et al. Nat. Rev. Dis. Primers (2016)

Clinical features:• Persistent parotid gland enlargement• Purpura• European League Against Rheumatism Sjögren syndrome Disease Activity Index(ESSDAI) score of ≥5

Genetic polymorphisms:• TNFSF13B• TNFRSF13C• TNFAIP3

Histopathological features:• Presence of germinal centers in the MSGB• Focus score of >3

Laboratory abnormalities:• CD4+ lymphopaenia

Immunological findings:• Low complement C3 or C4 levels• Mixed cryoglobulinaemia• MGUS• Increased lymphocyte-related cytokine levels (including BAFF,FMS-like tyrosine kinase 3 ligand, CXCL 13 and CXCL 11)• Increased β2-microglobulin levels• Presence of rheumatoid factor

Diagnostic modalities

Rischmueller M. et al Best Prac Res Clin Rheum (2016)

Lissamine staining as shown by slit-lamp examination

A. Punctate staining of the cornea.

B. Punctate staining of the conjunctival epithelium.

Kelley's Textbook of Rheumatology, 9th ed

Sialometry (USFR)• 5 or 15 minute whole saliva collection • Expectorate in pre-weighed container• Measure Pre and post- weight saliva

weight

Rischmueller M. et al Best Prac Res Clin Rheum (2016)

Cutoff: USFR < 0.1 ml/min

Autoantibodies in SS

• ANA: most common Ab: up to 85%Fabini G. et al. Eur. J. Biochem. (2000)

• SSA: 60-70%. Most specific. Predicts systemic involvement

• SSB: usually follows SSA. Caution if isolated• Rheumatoid factor: 50% risk of lymphoma

Minor Salivary Glands Biopsy (MSGB)

• Salivary glands contain secretory acini and ducts • Two types of secretions: serous and mucous • Acini are serous, mucous, or both

- Serous acini secrete proteins in watery fluid.

- Mucous acini secrete mucin

histology.leeds.ac.uk

Kim J et al. Laryngoscope. (2016)

Minor Salivary Gland Biopsy (MSGB)

• At least three salivary gland lobules• Examined area should be >=4 mm2

• Distinct pattern: Focal Lymphocytic Sialadenitis (FLS)

• A focus is >=50 lymphocytes in a cluster surrounding normal tissue

• If FLS present Focus score (FS) is calculated: FS is number of foci in 4 mm2

• Positive if FS >=1

Normal salivary gland

www.dartmouth.edu

Normal salivary gland

www.dartmouth.edu

Focal Lymphocytic Sialadenitis

Kim J et al. Laryngoscope. 2016

Other lab tests

• SPEP: Hyper or hypogammaglobulinemia. M-spike

Other lab tests

• SPEP: Hyper or hypogammaglobulinemia. M-spike• Complement C3 and C4. Predictor of poor outcome

Other lab tests

• SPEP: Hyper or hypogammaglobulinemia. M-spike• Complement C3 and C4. Predictor of poor outcome• Cryoglobulins: Predictor of poor outcome

Other lab tests

• SPEP: Hyper or hypogammaglobulinemia. M-spike• Complement C3 and C4. Predictor of poor outcome• Cryoglobulins: Predictor of poor outcome

• ESR and CRP• CBC: Neutropenia, Lymphopenia

Hemolytic anemia (rare)

• Consider Hepatitis C screen in all patients

Classification Criteria and diagnosis

Shiboski C et al. ARD and A&R (2017)

Classification Criteria

2016 ACR/EULAR criteria

Prognosis

Main causes of death:

• Lymphoma• Severe manifestations (ILD, renal failure, severe

cryoglobulinemic vasculitis)• infections and cardiovascular disease

Brito-Zerón, P. et al. Ann. Rheum. (2016)

Management

Management of Sicca syndrome

Management of dry mouth

o Prevention:• Dental visits• Avoid toxins (alcohol, smoking)• Avoid anticholinergics• Treat associated sinusitis/rhinitis• Fluoride compounds

o Replacement:• Mechanical stimulation of saliva • Saliva substitutes • Secretagogues

Secretagogues• For both dry mouth and eyes • Consider in:

- Excessive dental caries- Significant symptoms- Corneal damage

1. Pilocarpine 5-7.5 mg up to QID 2. Cevimeline 30 mg TID

• Side effects: Sweating, flushing, urinary frequency, GI • Caution if severe asthma / angle-closure glaucoma• Cevimeline has a better side effect profile

Noaiseh G, et al. Clin Exp Rheumatol. (2014)

Secretagogues• For both dry mouth and eyes • Consider in:

- Excessive dental caries- Significant symptoms- Corneal damage

1. Pilocarpine 5-7.5 mg up to QID 2. Cevimeline 30 mg TID

• Side effects: Sweating, flushing, urinary frequency, GI • Caution if severe asthma / angle-closure glaucoma• Cevimeline has a better side effect profile

Noaiseh G, et al. Clin Exp Rheumatol. (2014)

Management of dry eyes

• Mild, episodic symptoms:- Environmental modification may be enough

• Volume replacement and lubrication- Artificial tears and ointments/gels

• Topical anti-inflammatory therapy:Steroids - Cyclosporine - Lifitegrast - Autologous serum

• Secretagogues • Punctal occlusion/cauterization

Management of systemic manifestations

Hydroxychloroquine

• Commonly used for:- Fatigue- Arthralgia/Arthritis- Purpura

• Not useful in managing sicca symptoms

• Conflicting data in prospective studies• Support of use in retrospective studies

DMARDs in SSAzathioprine:• Price et al: placebo- controlled RCT, 25 pts, 6 months

- No significant change in disease activity variables Price EJ et al. J Rheumatol. (1998)

Cyclosporine:• Drosos et al: placebo-controlled RCT, 20 pts, 6 months, 5mg/kg

- Improvement of subjective dry mouth- No difference in objective dry mouth, parotid gland enlargement,

Schirmer’s and parotid flow rateDrosos AA et al Scand J Rheum. Suppl. (1986)

Methotrexate, Leflunomide, mycophenolate mofetil: • One prospective study for each agent

- Limited improvement in Sicca symptoms- High rate of adverse effects

Ramos-Casals M et al. JAMA. (2010)

Biologic therapy

• TNF inhibitors: No role• Rituximab:

- Negative studies - ?Helpful for vasculitic features

• Ongoing trials for Belimumab and Abatacept

• Other novel therapies

Conclusions• SS is the most common ANA-positive AID

Conclusions• SS is the most common ANA-positive AIRD• SS is not just the “disease of dry eyes and

mouth”

Conclusions• SS is the most common ANA-positive AID• SS is not just the “disease of dry eyes and

mouth”• Over 50% of SS patients have a benign course

but high-burden symptoms

Conclusions• SS is the most common ANA-positive AID• SS is not just the “disease of dry eyes and

mouth”• Over 50% of SS patients have a benign course

but high-burden symptoms• Many SS patients develop systemic

manifestations, some are severe

Conclusions• Among AI diseases, SS has the highest OR for

lymphoma development

Conclusions• Among AI diseases, SS has the highest OR for

lymphoma development • Patients with high disease activity need close

monitoring

Conclusions• Among AI diseases, SS has the highest OR for

lymphoma development • Patients with high disease activity need close

monitoring• Clinical/serological risk factors for Lymphoma

should be clarified/performed during evaluation

Questions ?